Dataset Information

FG-4592 Improves Depressive-Like Behaviors through HIF-1-Mediated Neurogenesis and Synapse Plasticity in Rats.

ABSTRACT: Depression, plus the accompanying memory impairment, is one of the leading causes of disability worldwide. Thus, there is a critical need to develop new drugs based on distinct strategies. FG-4592, an inhibitor of prolyl hydroxylase, activates the hypoxia-inducible factor-1 (HIF-1) pathway, to produce multiple effects on cell properties. Here, we examined whether FG-4592 has antidepressant effects, using a chronic unpredictable mild stress (CUMS) procedure to establish rodent depression models. We found that FG-4592 not only reversed depressive behaviors but also improved CUMS-induced memory impairment. Mechanistically, FG-4592 could play an important role in promoting hippocampal neurogenesis and synaptic plasticity. At the molecular level, FG-4592 was found to activate HIF-1 and cAMP-responsive element-binding protein/brain-derived neurotrophic factor signaling pathways in vivo, as well as promote the expression of postsynaptic density (PSD) proteins, PSD95 and Homer1. An examination of primary hippocampal neurons showed that FG-4592 promoted dendritic growth. Taken together, our results not only provide an experimental basis for the future application of FG-4592 in clinical treatment of depression but also support the argument that the HIF-1 signaling pathway is a promising target for the treatment of depression.

SUBMITTER: Li G

PROVIDER: S-EPMC7283439 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

FG-4592 Improves Depressive-Like Behaviors through HIF-1-Mediated Neurogenesis and Synapse Plasticity in Rats.

Li Gaifen G Zhao Ming M Cheng Xiang X Zhao Tong T Feng Zhenlong Z Zhao Yongqi Y Fan Ming M Zhu Lingling L

Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics 20200401 2

Depression, plus the accompanying memory impairment, is one of the leading causes of disability worldwide. Thus, there is a critical need to develop new drugs based on distinct strategies. FG-4592, an inhibitor of prolyl hydroxylase, activates the hypoxia-inducible factor-1 (HIF-1) pathway, to produce multiple effects on cell properties. Here, we examined whether FG-4592 has antidepressant effects, using a chronic unpredictable mild stress (CUMS) procedure to establish rodent depression models. ...[more]

PMID: 31820273

Similar Datasets

Project description:Increasing evidence indicates that the pathogenesis of depression is closely linked to impairments in neuronal synaptic plasticity. Honokiol, a biologically active substance extracted from Magnolia Officinalis, has been proven to exert significant antidepressant effects. However, the specific mechanism of action remains unclear. In this study, PC12 cells and chronic unpredictable mild stress (CUMS) model rats were used to explore the antidepressant effects and potential mechanisms of honokiol in vitro and in rats. In vitro experiment, a cell viability detection kit was used to screen the concentration and time of honokiol administration. PC12 cells were administered with hypoxia-inducible factor-1α (HIF-1α) blocker, 2-methoxyestradiol (2-ME), and vascular endothelial growth factor receptor 2 (VEGFR-2) blocker, SU5416, to detect the expression of HIF-1α, VEGF, synaptic protein 1 (SYN 1), and postsynaptic density protein 95 (PSD 95) by western blotting. In effect, we investigated whether the synaptic plasticity action of honokiol was dependent on the HIF-1α-VEGF pathway. In vivo, behavioral tests were used to evaluate the reproducibility of the CUMS depression model and depression-like behaviors. Molecular biology techniques were used to examine mRNA and protein expression of the HIF-1α-VEGF signaling pathway and synaptic plasticity-related regulators. Additionally, molecular docking techniques were used to study the interaction between honokiol and target proteins, and predict their binding patterns and affinities. Experimental results showed that honokiol significantly reversed CUMS-induced depression-like behaviors. Mechanically, honokiol exerted a significant antidepressant effect by enhancing synaptic plasticity. At the molecular level, honokiol can activate the HIF-1α-VEGF signaling pathway in vitro and in vivo, as well as promote the protein expression levels of SYN 1 and PSD 95. Taken together, the results do not only provide an experimental basis for honokiol in the clinical treatment of depression but also suggest that the HIF-1α-VEGF pathway may be a potential target for the treatment of depression.

Project description:Incomplete recovery from acute kidney injury induced by folic acid is a major risk factor for progression to chronic kidney disease. Mitochondrial dysfunction has been considered a crucial contributor to maladaptive repair in acute kidney injury. Treatment with FG-4592, an inhibitor of hypoxia inducible factor prolyl-hydroxylase, is emerging as a new approach to attenuate renal damage; however, the underlying mechanism has not been fully elucidated. The current research demonstrated the protective effect of FG-4592 against renal dysfunction and histopathological damage on the 7th day after FA administration. FG-4592 accelerated tubular repair by promoting tubular cell regeneration, as indicated by increased proliferation of cell nuclear antigen-positive tubular cells, and facilitated structural integrity, as reflected by up-regulation of the epithelial inter-cellular tight junction molecule occludin-1 and the adherens junction molecule E-cadherin. Furthermore, FG-4592 ameliorated tubular functional recovery by restoring the function-related proteins aquaporin1, aquaporin2, and sodium chloride cotransporter. Specifically, FG-4592 pretreatment inhibited hypoxia inducible factor-1α activation on the 7th day after folic acid injection, which ameliorated ultrastructural abnormalities, promoted ATP production, and attenuated excessive reactive oxygen species production both in renal tissue and mitochondria. This was mainly mediated by balancing of mitochondrial dynamics, as indicated by down-regulation of mitochondrial fission 1 and dynamin-related protein 1 as well as up-regulation of mitofusin 1 and optic atrophy 1. Moreover, FG-4592 pretreatment attenuated renal tubular epithelial cell death, kidney inflammation, and subsequent interstitial fibrosis. In vitro, TNF-α-induced HK-2 cells injury could be ameliorated by FG-4592 pretreatment. In summary, our findings support the protective effect of FG-4592 against folic acid-induced mitochondrial dysfunction; therefore, FG-4592 treatment can be used as a useful strategy to facilitate tubular repair and mitigate acute kidney injury progression.

Dataset Information

FG-4592 Improves Depressive-Like Behaviors through HIF-1-Mediated Neurogenesis and Synapse Plasticity in Rats.

Publications

FG-4592 Improves Depressive-Like Behaviors through HIF-1-Mediated Neurogenesis and Synapse Plasticity in Rats.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets